What side effects are associated with this type of intervention?

Common treatments for colorectal cancer, such as Nivolumab (a PD-1 inhibitor), Trametinib (a MEK inhibitor), and Ipilimumab (a CTLA-4 inhibitor), have distinct side effect profiles. Nivolumab often causes fatigue, rash, diarrhea, and immune-related adverse events like pneumonitis and colitis. Trametinib is associated with rash, diarrhea, peripheral edema, and cardiomyopathy. Ipilimumab can lead to severe immune-mediated reactions including colitis, dermatitis, hepatitis, and endocrinopathies. Combining these therapies may increase the risk and severity of these side effects.

What prior FDA approvals exist?

Nivolumab, a PD-1 inhibitor, has been approved by the FDA for the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Ipilimumab, a CTLA-4 inhibitor, has also been approved in combination with Nivolumab for the same indication. However, Trametinib, a MEK inhibitor, is not currently approved for colorectal cancer treatment. These approvals highlight the use of immune checkpoint inhibitors in specific genetic subtypes of colorectal cancer.

What other types of research exist?

Promising novel alternatives for colorectal cancer treatment in 2024 include: <ol> <li>Pembrolizumab (PD-1 Inhibitor): Effective for patients with dMMR or high TMB.</li> <li>Dostarlimab (PD-1 Inhibitor): Another option for dMMR colorectal cancer.</li> <li>Combination of PD-1/PD-L1 inhibitors with chemotherapy: This approach has shown higher response rates and progression-free survival in other cancers and is being explored in colorectal cancer.</li> <li>Emerging biomarkers and personalized medicine: Genomic testing to identify actionable mutations can guide the use of targeted therapies and immunotherapies tailored to individual patient profiles.</li> </ol>

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Checkpoint Inhibitor

Nivolumab + Trametinib (+/- Ipilimumab) for Colorectal Cancer (CheckMate 9N9 Trial)

Phase 1 & 2

Waitlist Available

Research Sponsored by Bristol-Myers Squibb

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 at screening and on cycle 1 day 1 (C1D1)

Histologically or cytologically confirmed previously treated metastatic colorectal cancer with adenocarcinoma histology and in Stage IV per American Joint Committee on Cancer (version 4.0) at study entry

Must not have

History of interstitial lung disease or pneumonitis

BRAF V600 mutant colorectal cancer

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 100 months

Awards & highlights

Summary

This trial is looking at a new combination treatment for people with colon or rectal cancer that has spread and who have already been treated.

Who is the study for?

This trial is for individuals with Stage IV colorectal cancer that has spread and was previously treated. They must have measurable disease, be in good physical condition (ECOG 0-1), and not have certain genetic mutations (BRAF V600). People can't join if they've had brain metastases, need systemic steroids or immunosuppressants, are allergic to the drugs being tested, or have used checkpoint inhibitors/MEK inhibitors before.Check my eligibility

What is being tested?

The study tests nivolumab combined with trametinib, with some participants also receiving ipilimumab. It aims to see how well these drugs work together in treating colorectal cancer that's spread after previous treatment. Participants will be randomly assigned to different drug combinations.See study design

What are the potential side effects?

Possible side effects include immune-related reactions affecting organs like the lungs (pneumonitis), skin issues, fatigue, digestive problems such as diarrhea or colitis, liver inflammation (hepatitis), hormonal gland issues like thyroid disorders and adrenal insufficiency.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am fully active or restricted in physically strenuous activity but can do light work.

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My colorectal cancer is confirmed to be in stage IV and has been previously treated.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have had interstitial lung disease or pneumonitis.

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My colorectal cancer has a BRAF V600 mutation.

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I have an autoimmune disease.

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I have been treated with drugs targeting the immune system and MEK enzymes.

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I have active cancer spread to my brain or its coverings.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 100 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 100 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 100 months for reporting.

Treatment Details

Study Objectives

Outcome measures can provide a clearer picture of what you can expect from a treatment.

Primary outcome measures

Incidence of dose limiting toxicity (DLTs)

Objective response rate (ORR) by investigator (Part 1B and Part 2)

Secondary outcome measures

Best overall response (BOR)

Disease control rate (DCR)

Duration of response (DOR)

+10 more

Side effects data

From 2022 Phase 3 trial • 541 Patients • NCT02041533

57%

Nausea

54%

Anaemia

51%

Fatigue

39%

Decreased appetite

36%

Malignant neoplasm progression

32%

Constipation

31%

Diarrhoea

30%

Cough

29%

Vomiting

29%

Dyspnoea

25%

Oedema peripheral

24%

Back pain

21%

Neutropenia

21%

Pyrexia

19%

Headache

19%

Hypomagnesaemia

18%

Arthralgia

16%

Asthenia

16%

Dizziness

16%

Neutrophil count decreased

15%

Thrombocytopenia

15%

Insomnia

14%

Hyponatraemia

14%

Rash

14%

Weight decreased

14%

Platelet count decreased

13%

Blood creatinine increased

13%

White blood cell count decreased

12%

Hypokalaemia

12%

Pruritus

12%

Abdominal pain

12%

Pain in extremity

11%

Myalgia

11%

Alanine aminotransferase increased

11%

Aspartate aminotransferase increased

10%

Alopecia

10%

Dry skin

10%

Hypoalbuminaemia

10%

Muscular weakness

10%

Chest pain

10%

Dysgeusia

10%

Pneumonia

10%

Productive cough

Hypothyroidism

Abdominal pain upper

Upper respiratory tract infection

Mucosal inflammation

Peripheral sensory neuropathy

Lacrimation increased

Nasopharyngitis

Non-cardiac chest pain

Epistaxis

Haemoptysis

Stomatitis

Dysphonia

Chills

Hypertension

Bronchitis

Dehydration

Blood alkaline phosphatase increased

Hyperglycaemia

Hyperkalaemia

Lymphocyte count decreased

Anxiety

Hypophosphataemia

Leukopenia

Pleural effusion

Neuropathy peripheral

Pneumonitis

Oropharyngeal pain

Hypotension

Dry mouth

Pain

Malaise

Musculoskeletal chest pain

Rash maculo-papular

Urinary tract infection

Dyspepsia

Gamma-glutamyltransferase increased

Depression

Muscle spasms

Fall

Pulmonary embolism

Myocardial infarction

Metastases to central nervous system

Febrile neutropenia

Musculoskeletal pain

Chronic obstructive pulmonary disease

Embolism

Cardiac failure

Malignant pleural effusion

Sepsis

Atrial fibrillation

General physical health deterioration

Adrenal insufficiency

Neoplasm progression

Cancer pain

Confusional state

Circulatory collapse

Bronchial obstruction

Pneumothorax

Atrial flutter

Ileus

Bone pain

Small intestinal haemorrhage

Pericardial effusion

Femur fracture

Pancytopenia

Colitis

Small intestinal obstruction

Hypercalcaemia

Syncope

Pericardial effusion malignant

Superior vena cava syndrome

Gastrointestinal haemorrhage

Lung cancer metastatic

Performance status decreased

Respiratory tract infection

Respiratory failure

Tumour pain

Appendicitis

Skin infection

Ataxia

Seizure

100%

80%

60%

40%

20%

Study treatment Arm

Investigator Choice of Chemotherapy

Post Chemotherapy Optional Nivolumab

Nivolumab

Trial Design

6Treatment groups

Experimental Treatment

Group I: Part 2 Cohort 5 (3L): RegorafenibExperimental Treatment1 Intervention

Group II: Part 2 Cohort 4 (3L): nivolumab + ipilimumab + trametinibExperimental Treatment3 Interventions

Group III: Part 1B Cohort 6 (2L): nivolumab + ipilimumab + trametinibExperimental Treatment3 Interventions

Group IV: Part 1A Cohort 3 (2L): nivolumab + ipilimumab + trametinibExperimental Treatment3 Interventions

Group V: Part 1A Cohort 2 2nd Line (2L): nivolumab + ipilimumab + trametinibExperimental Treatment3 Interventions

Group VI: Part 1 Cohort 1 3rd Line (3L): nivolumab + trametinibExperimental Treatment2 Interventions

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Trametinib

2014

Completed Phase 2

~1550

Regorafenib

2014

Completed Phase 2

~1580

Ipilimumab

2014

Completed Phase 3

~2610

Nivolumab

2014

Completed Phase 3

~4740

0 / 7Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for colorectal cancer include immune checkpoint inhibitors and targeted therapies. Nivolumab, a PD-1 inhibitor, works by blocking the programmed cell death protein 1 (PD-1) pathway, thereby enhancing the immune system's ability to attack cancer cells. Trametinib, a MEK inhibitor, targets the MEK enzyme in the MAPK/ERK pathway, which is often overactive in cancer cells, leading to reduced tumor growth. Ipilimumab, a CTLA-4 inhibitor, blocks the CTLA-4 protein on T cells, boosting the immune response against cancer cells. These mechanisms are crucial for colorectal cancer patients as they offer a way to target cancer cells more precisely and enhance the body's immune response, potentially leading to better outcomes.

Targeted Therapy and Checkpoint Immunotherapy Combinations for the Treatment of Cancer.